PROJECT 2 DESCRIPTION: This project will define, via studies performed in rhesus macaques, the most effective and technically simplest methods to administer MVA-based HIV vaccines. The epidermal and dermal layers of the skin, anatomic compartments exceptionally rich in dendritic cells, constitute active immunologic sites that may be easily targeted for noninvasive delivery of vaccines. We will compare the immunogenicity of our MVA-based vaccines when targeted to the epidermis, the dermis or muscle. We will determine the route of MVA vector administration that elicits the best immune responses; determine how route of MVA (and other priming vector) administration affects the function and homing properties (including to mucosal tissues) of vaccine-elicited HIV-specific immune effector cells; exploit MVA's predilection for infection of antigen presenting cells to elicit high-level HIV-antigen-specific immune responses via recruitment of antigen presenting cells (APCs) to the site of virus inoculation; and explore and develop novel needle-free immunization strategies that may be safer, more affordable and more effective in resource-poor countries. This project will: 1) characterize dermabrasion in both rhesus macaques and humans as a simple means by which to access the epidermis, 2) compare the immunogenicity of vaccines deposited to the epidermis, the dermis and muscle of macaques, 3) determine how the inclusion of different DC-recruiting chemokines, either encoded by a recombinant MVA or co-administered with the vaccine inoculation as a recombinant protein, affects MVA immunogenicity, and 4) explore novel methods of inducing mucosal immunity and determine whether the induction of mucosal immunity is primarily determined at the priming or boosting phase of an immunization regimen.